Atherothrombotic vascular disease and Ml are the leading cause of sudden death and disability worldwide. This necessitates the development of new strategies towards slowing progression of atherosclerotic and CVD disease. According to recent findings in experimental animals and humans, a major feature of advanced, rupture-prone atherosclerotic plaque is defective clearance of apoptotic cells. Apoptotic cell death, in the absence of efficient phagocytic clearance (efferocytosis), promotes post-apoptotic necrosis, which contributes to inflammation and plaque disruption. Surprisingly, though numerous candidates have been implicated, the key factors that lead to defective efferocytosis in-vivo have yet to be elucidated. We have recently discovered that deficiency of the cell surface receptor MERTK, reduces efferocytosis in murine lesions and promotes key features of plaque vulnerability, namely necrotic core expansion. Interestingly, preliminary data also suggest that advanced coronary disease in humans coincides with proteolytic degradation of MERTK. To determine if MERTK proteolysis contributes to plaque destabilization, we have engineered a cleavage-resistant MERTK. In-vitro, MERTK proteolysis is driven by inflammation. In-vivo, an inflammatory Ly6C-HI monocyte subset is recruited to atherosclerotic lesions and post myocardial infarcts and differentiate into macrophage phagocytes. In collaborative work, we have found that Ly6C-HI monocytes differentiate into a subset of phagocytes with poor in-vitro efferocytosis efficiency. We hypothesize that plaque vulnerability and maladaptive post Ml repair is promoted by inflammatory phagocyte subsets with reduced functional MERTK and poor efferocytosis efficiency. We will elucidate the molecular mechanisms that regulate efferocytosis efficiency of phagocyte subpopulations both in vitro and in vivo. This overall concept presents an opportunity for novel therapeutic strategies directed against progression of inflammation and CVD, namely through the elucidation of mechanisms that control in-vivo efferocytosis efficiency and modalities aimed at restoration and augmentation of defective efferocytosis.